Anthelmintic formulations

ABSTRACT

A veterinary composition containing an effective amount of praziquantel, an effective amount of at least one macrolide anthelmintic selected from the group comprising the avermectins and the milbemycins, and a suitable organic solvent selected from the group consisting of glycerol formal, ethyl lactate, benzyl alcohol and N-methyl-2-pyrrolidone and the like wherein the composition is suitable for administration to warm-blooded non-human animals. The composition may be a solution or a paste and may be administered to the recipient animal by injection, drench or as an oral paste. A method of treating endo- and ectoparasites in non-human animals is also claimed.

This application is a 371 of PCT/NZ97/00096 filed Jul. 25, 1997.

TECHNICAL FIELD OF THE INVENTION

This invention relates to solutions containing the anthelmintic, praziquantel.

BACKGROUND

In recent years the new anthelmintic compounds of the macrolide group such as avermectins and milbemycins have been drugs of choice for the treatment of internal parasites of sheep, cattle and other farm animals. These compounds offer not only the control of many internal parasites but also external parasites and therefore have become known as endecticides. Their popularity has increased because of their dual activity and because of increasing resistance to other traditional anthelmintics like levamisole and the benzimidazoles.

However, unlike the benzimidazoles, the macrolide anthelmintics need to be administered as solutions to be bio-available as in their solid form they are poorly absorbed by the animal. It has therefore been the practice to formulate these compounds by dissolving them in solvents before administration.

Some types of parasites, particularly trematodes, that are not controlled by the macrolide endecticides. Important trematodes in sheep for example are Liver Fluke (Fasciola hepatica) and Tapeworm (Monezia spp.).

Previous methods of incorporating anthelmintics that have activity against trematodes have relied on suspending a compound like praziquantel that controls Monezia spp. in an anthelmintic solution. It is more desirable to have dual formulations as solutions as this allows wider application as injectables or drenches.

OBJECT

It is an object of this invention to provide a composition containing an effective amount of praziquantel and at least one of the active anthelmintics of the macrolide group or at least one that provides the public with a useful choice.

STATEMENT OF INVENTION

In one aspect the invention comprises veterinary composition containing:

a) an effective amount of praziquantel;

b) an effective amount at least one macrolide anthelmintic selected from the group comprising the avermectins and the milbemycins; and

c) a suitable organic solvent capable of dissolving a) and b);

wherein the composition is suitable for administration to warm-blooded non-human animals.

Preferably the solvent is an ester or ester-like compound. Certain esters and similar compounds have the benefit of dissolving both praziquantel and the avermectins and milbemycins without being toxic to animals.

More preferably the solvent is selected from the group consisting of glycerol formal, ethyl lactate, benzyl alcohol, N-methyl-2-pyrrolidone and the like.

Preferably the composition is further dissolved in a carrier selected from the group consisting of monoproylene glycol, oil, water and the like.

Preferably the composition is a solution.

Preferably the macrolide anthelmintic is present in the composition in the range from 0.1-2% w/v and the praziquantel is preferably present in the composition in the range from 1-10% w/v.

Alternatively the composition is a paste containing:

(a) a solution of an effective amount of praziquantel, an effective amount at least one macrolide anthelmintic selected from the group comprising the avermectins and the milbemycins, and a suitable organic solvent; and

(b) a thickener.

Preferably the thickener is a solid carrier onto which the solution is absorbed and is selected from the group comprising oat meal flour, methancel, and xanthan gum.

Preferably the macrolide anthelmintic is present in the paste in the range from 0.1-2% w/v and the praziquantel is preferably present in the composition in the range from 1-10% w/v.

In another aspect the invention provides a method for the treatment of endo- and ectoparasites in a non-human animal by administering to an animal a composition as described above at the rate of 1 ml/5-20 kg of bodyweight.

Preferably the animal is treated every 6-8 weeks or more often as required.

Preferably the composition is administered to the animal as a drench, by injection or as an oral paste.

PREFERRED EMBODIMENT

These and other aspects of this invention, which should be considered in all its novel aspects will be apparent from the following examples.

EXAMPLE 1

Formulation Type: Drench

Intended Recipient Animals: Sheep, Cattle, Goats

    ______________________________________                                         Ingredient              % w/v                                                  ______________________________________                                         Ivermectin               0.2                                                     Praziquantel  4.0                                                              Tween 80 10.0                                                                  Glycerol Formal 10.0                                                           Benzyl Alcohol  4.0                                                            Propyl Gallate  0.009                                                          Monopropylene Glycol 40.0                                                      Deionised water 20.0                                                           Disodium EDTA  0.009                                                           Sodium dihydrogen phosphate  0.5                                               Disodium hydrogen phosphate  0.5                                               Mineral Premix 10.0                                                            Selenium Chelate  0.305                                                        Monopropylene Glycol To volume                                                  100.0 mL                                                                    ______________________________________                                    

The mineral premix is a chelated mineral mixture of Copper, Cobalt and Zinc.

Example 1 is manufactured as follows:

1. To a clean dry mixing vessel add the benyl alcohol and with stirring add the ivermectin. Stir until completely dissolved.

2. Add the Tween 80 and glycerol formal and stir until completely dispersed.

3. Add the praziquantel while stirring and warm the solution to 50-60° C. Continue stirring until fully dissolved.

4. Add the propyl gallate and stir until dissolved.

5. Add the monopropylene glycol and stir to mix.

6. To a separate mixing vessel add the deionised water and with stirring add the disodium EDTA, sodium dihydrogen phosphate and disodium hydrogen phosphate in order ensuring each is fully dissolved before the next is added.

7. Add the sodium chelate and stir until fully dissolved.

8. Add the mineral premix and stir well to mix.

9. With stirring add the water phase to the solvent phase and stir until fully mixed (should be a clear dark blue solution).

10. Make up volume with monopropylene glycol and stir well to mix.

11. Package the product in appropriate packaging.

EXAMPLE 2a

Formulation Type: Drench

Intended Recipient Animal: Sheep, Cattle, Goats

    ______________________________________                                         Ingredient              % w/v                                                  ______________________________________                                         Ivermectin               0.1                                                     Praziquantel  1.88                                                             Tween 80 10.0                                                                  Glycerol Formal 10.0                                                           Benzyl Alcohol  4.0                                                            Propyl Gallate  0.009                                                          Monopropylene Glycol 40.0                                                      Deionised water 20.0                                                           Disodium EDTA  0.009                                                           Sodium dihydrogen phosphate  0.5                                               Disodium hydrogen phosphate  0.5                                               Mineral Premix 10.0                                                            Selenium Chelate  0.305                                                        Monopropylene Glycol To volume                                                  100.0 mL                                                                    ______________________________________                                    

The mineral premix is a chelated mineral mixture of Copper, Cobalt and Zinc.

EXAMPLE 2b

Formulation Type: Drench

Intended Recipient Animal: Sheep, Cattle, Goats

    ______________________________________                                         Ingredient              % w/v                                                  ______________________________________                                         Abamectin                0.1                                                     Praziquantel  1.88                                                             Tween 80 10.0                                                                  Glycerol Formal 10.0                                                           Benzyl Alcohol  4.0                                                            Propyl Gallate  0.009                                                          Monopropylene Glycol 40.0                                                      Deionised water 20.0                                                           Disodium EDTA  0.009                                                           Sodium dihydrogen phosphate  0.5                                               Disodium hydrogen phosphate  0.5                                               Mineral Premix 10.0                                                            Selenium Chelate  0.305                                                        Monopropylene Glycol To volume                                                  100.0 mL                                                                    ______________________________________                                    

The mineral premix is a chelated mineral mixture of Copper, Cobalt and Zinc.

Examples 2a and 2b are manufactured as follows:

1. To a clean dry mixing vessel add the benzyl alcohol and with stirring add the ivermectin or abamectin. Stir until completely dissolved.

2. Add the Tween 80 and glycerol formal and stir until completely dispersed.

3. Add the praziquantel while stirring and warm the solution to 50-60° C. Continue stirring until fully dissolved.

4. Add the propyl gallate and stir until dissolved.

5. Add the monopropylene glycol and stir to mix.

6. To a separate mixing vessel add the deionised water and with stirring add the disodium EDTA, sodium dihydrogen phosphate and disodium hydrogen phosphate in order ensuring each is fully dissolved before the next is added.

7. Add the sodium chelate and stir until fully dissolved.

8. Add the mineral premix and stir well to mix.

9. With stirring add the water phase to the solvent phase and stir until fully mixed (should be a clear dark blue solution).

10. Make up volume with monopropylene glycol and stir well to mix.

11. Package the product in appropriate packaging.

EXAMPLE 3

Formulation Type: Drench

Intended Recipient Animals: Sheep, Cattle, Goats

    ______________________________________                                         Ingredient             % w/v                                                   ______________________________________                                         Abamectin               0.113                                                    Praziquantel  1.88                                                             Selenium (Na.sub.2 Se)  0.305                                                  Mineral Premix 10.00                                                           Polysorbate 80 BP  5.00                                                        Benzyl Alcohol BP  2.00                                                        Ethyl Lactate 10.00                                                            Potassium Sorbate  0.18                                                        Formalin  0.20                                                                 Purified water BP 20.00                                                        Sodium Phosphate BP  0.10                                                      Sodium Acid Phosphate  0.90                                                    Propylene Glycol BP to volume                                                   100.0 mL                                                                    ______________________________________                                    

The mineral premix is a chelated mineral mixture of Copper, Cobalt and Zinc.

Example 3 is manufactured as follows:

1. To a clean dry mixing vessel add the ethyl lactate, benzyl alcohol and Polysorbate 80.

2. While stirring add the abamectin and praziquantel and stir until dissolved.

3. To a separate mixing vessel add the water and dissolve in the potassium sorbate.

4. Add the sodium phosphate and sodium acid phosphate and stir until fully dissolved.

5. Add the selenium and mineral premix and stir to dissolve.

6. Add the water mix to the abamectin/praziquantel mix and stir well to mix.

7. Add the formalin and stir well.

8. Make up to volume with the propylene glycol.

9. Package the product in suitable container.

Examples 1, 2a, 2b and 3 produce stable solutions that are aqueous based. They may be administered at a rate of 1 mL/5-20 kg of bodyweight of the animal every 6-8 weeks or as required.

EXAMPLE 4

Formulation Type: Oral Paste

Intended Recipient Animals: Horses and Companion Animals

    ______________________________________                                         Ingredient                % w/v                                                ______________________________________                                         Abamectin                  0.400                                                 Praziquantel  5.000                                                            DiEthylene Glycol Palmito Stearate (DEGPS)  8.000                              Oat Meal Flour 30.00                                                           Sodium Metabisulfite  0.100                                                    Sorbitol Solution (non-crystallising) 12.00                                    Glycerol Formal  6.000                                                         PolyEthylene Glycol 400  6.000                                                 Methyl Hydroxybenzoate  0.050                                                  Propyl Hydroxybenzoate  0.005                                                  Benzyl Alcohol  1.000                                                          Purified Water To volume                                                        100.0 mL                                                                    ______________________________________                                    

Example 4 is manufactured as follows:

1. In a separate container, heat purified water to 80-85°. Maintain at this temperature.

2. While mixing, add and dissolve methyl hydroxybenzoate and propyl hydroxybenzoate. Continue mixing until all has dissolved.

3. While mixing, add sorbitol solution. Maintain the temperature at 70° C.

4. In a separate container add glycerol formal, polyethylene glycol 400 and benzyl alcohol. Start mixing while warming to 35-40° C.

5. While mixing, add abamectin. Continue mixing until all has dissolved. Maintain temperature at 35-40° C.

6. In the ointment tank add half the oat meal flour and the praziquantel and then start mixing. Continue mixing for 5-10 minutes then add the rest of the oat meal flour and continue mixing until a homogenous blended powder is formed.

7. While mixing the powders add the solution from step 5 in a thin stream. When all is added continue mixing until a homogenous mass is formed.

8. Melt DiEthylene Glycol Palmito Stearate (DEGPS) in a separate container. While mixing the solution from step 3, add the melted wax and continue mixing to form an homogenous emulsion. Stop heating and mix to cool to 40-45° C.

9. Add and dissolve sodium metabisulfite in the emulsion.

10. While mixing the mass from step 7, add gradually and in a thin stream the emulsion from step 9. Emulsion when added should be at 40-45° C.

11. When all is added continue mixing for 10-15 minutes descaping the walls occassionally.

12. Complete the batch to volume with purified water while mixing. Continue mixing for 30 minutes. Stop when the batch temperature is not higher than 30° C. Check the specific gravity (1.05-1.09).

13. Homogenise the batch. When completed the batch is in the form of a smooth paste, free from lumps or grittiness, beige in colour and has a pleasant characteristic odour.

14. Package in paste syringes.

In example 4 oat meal flour is used as a solid carrier. Other examples of solid carriers that could be used are methancel or xanthan gum.

Example 4 produces a spreadable, viscous paste which may be administered to an animal as an oral paste at the rate of 1 mL/5-20 kg of bodyweight of the animal every 6-8 weeks or as required. The formulation is aqueous based.

EXAMPLE 5

Formulation Type: Drench

Intended Recipient Animals: All Farm Animals

    ______________________________________                                         Ingredient            % w/v                                                    ______________________________________                                         Abamectin              0.100                                                     Praziquantel  1.880                                                            Benzyl Alcohol 10.00                                                           Soyabean oil To volume                                                          100.0 mL                                                                    ______________________________________                                    

Example 5 is preferably manufactured as follows:

1. To a clean dry mixing vessel add the Benzyl Alcohol, and while stirring add the Abamectin and Praziquantel. Continue to stir until completely dissolved.

2. Make up to volume with the Soyabean Oil and stir well to mix.

3. Package the product in suitable packaging.

Example 5 produces a solution that is oil based. It may be administered at a rate of 1 mL/5-20kg of bodyweight of the animal every 6-8 weeks or as required.

EXAMPLE 6

Formulation Type: Injectable

Intended Recipient Animals: All Farm Animals

    ______________________________________                                         Ingredient             % w/v                                                   ______________________________________                                         Abamectin               1.22                                                     Praziquantel 15.0                                                              Glycerol Formal 60.0                                                           Monopropylene Glycol To volume                                                  100.0 mL                                                                    ______________________________________                                    

Example 6 is manufactured as follows:

1. To a clean dry mixing vessel add the glycerol formal and while stirring add the abamectin and praziquantel. Continue to stir until dissolved.

2. Make up to volume with monopropylene glycol and stir well.

3. Sterilise product by suitable filtration and pack under sterile conditions into suitable injection bottles.

Example 6 produces a solution that is suitable for injection. It may be administered at a rate of 1 mL/5-20kg of bodyweight of the animal every 6-8 weeks or as required.

EXAMPLE 7

Formulation Type: Injection or Drench

Intended Recipient Animals: All Farm Animals

    ______________________________________                                         Ingredient             % w/v                                                   ______________________________________                                         Abamectin               1.22                                                     Praziquantel 15.0                                                              N-Methyl-2-Pyrolidone 60.0                                                     Sesame Oil To volume                                                            100.0 mL                                                                    ______________________________________                                    

Example 7 is manufactured as follows:

1. To a clean dry mixing vessel add the glycerol formal and while stirring add the abamectin and praziquantel. Continue to stir until dissolved.

2. Make up to volume with sesame oil and stir well.

3. Package product under sterile conditions into suitable injection bottles or in suitable containers for a drench formulation.

Example 7 produces an oil based solution that is suitable for administration as an injection or a drench. It may be administered at a rate of 1 mL/5-20 kg of bodyweight of the animal every 6-8 weeks or as required.

The compositions of the invention are stable and have been shown to be non-toxic to animals.

STABILITY EXAMPLE 3 Stability Trial

A solution according to example 3 was prepared and tested for stability. The solution was stored at ambient temperature in a black high density polyethylene container with a black high density polyethylene cap.

A variety of tests were performed on the composition initially, and then at 3 months, 6 months and one year. The results are set out in Table 1.

                                      TABLE 1                                      __________________________________________________________________________     Stability of Example 3                                                         Test      Initial 3 Months                                                                               6 Months                                                                               1 Year                                       __________________________________________________________________________     Appearance                                                                               Clear, blue liquid                                                                     Clear, blue liquid                                                                     Clear, blue liquid                                                                     Clear, blue liquid                             Appearance after Okay Okay Okay Okay                                           inversion                                                                      Density at 20° C. 1.062 1.063 1.065 1.067                               (g/mL)                                                                         Viscosity at 20° C. 14 14 14 14                                         Ford #4 Cup                                                                    (Seconds)                                                                      Bottle condition Okay Okay Okay Okay                                           pH 6.7 6.4 5.8 5.8                                                             Praziquantel (g/L) 18.9 17.9 18.9:18.9* 18.9                                   Abamectin (g/L) 1.09 1.00 1.03:1.04* 0.95                                      MINERAL PREMIX                                                                 Copper (g/L) 2.12 2.19 2.24 2.23                                               Cobalt (g/L) 0.24 0.21 0.20:0.21* 0.20:0.20                                    Zinc (g/L) 0.61 0.60 0.58:0.56* 0.63                                           Selenium (g/L) 0.45 0.49 0.48 0.50:0.50                                      __________________________________________________________________________      [*Repeat assays carried out where first assay result was in doubt        

There was no loss of stability of the composition over the trial period.

Copper, cobalt and zinc are included in the mineral premix of example 3. Selenium is added separately to the composition.

EXAMPLE 4 Stability Trial

A spreadable paste according to example 4 was prepared and tested for stability at 30° C. and at 40° C.

The paste was stored in a plastic syringe inside a carton.

The amount of the active ingredients was measured initially, and then at one month, three months and six months. The results are set out below in Table 2 and Table 3.

                  TABLE 2                                                          ______________________________________                                         Stability of Example 4 at 30° C.                                                   Initial 1 Month   3 Months                                                                               6 Months                                  ______________________________________                                         Abamectin (g/kg)                                                                          3.5     3.7       3.6     3.6                                         Total Avermectin 3.7 3.9 3.8 3.8                                               (g/kg)                                                                         Praziquantel 50 50 46 48                                                       (g/kg)                                                                       ______________________________________                                          [Differences in Abamectin and Total Avermectin concentrations over the         trial period was within the margin of error for the trial                

                  TABLE 3                                                          ______________________________________                                         Stability of Example 4 at 40° C.                                                   Initial 1 Month   3 Months                                                                               6 Months                                  ______________________________________                                         Abamectin (g/kg)                                                                          3.5     3.4       3.1     3.4                                         Total Avermectin 3.7 3.6 3.3 3.7                                               (g/kg)                                                                         Praziquantel 50 48 48 49                                                       (g/kg)                                                                       ______________________________________                                          [Differences in Abamectin and Total Avermectin concentrations over the         trial period was within the margin of error for the trial                

EFFICACY

The efficacy of example 3 (Speedwell P Mineral Drench for Sheep) and example 3 without praziquantel (Speedwell Mineral Drench for Sheep) in the control and treatment of naturally occurring infection with common pathogenic nematodes and cestodes was assessed against the commercially available product Ivomec Liquid for Sheep and Goats (Merck Sharp & Dohme).

The study and interpretation of the raw data was undertaken in accordance with the World Association for the Advancement of Veterinary Parasitology (WAAVP) guidelines.

Abamectin stimulates the release of a neurotransmitter, gamma aminobuteryic acid (GABA) from the nerve endings and enhances its binding to GABA receptors at the nerve junctions. This action interrupts nerve impulses and leads to paralysis and death. It has no effect against cestodes, trematodes nor the mammalian peripheral nervous system.

Praziquantel inhibits cestode carbohydrate metabolism.

Allocation of Test Animals

Thirty-two clinically healthy Romney hoggets were used. The hoggets were selected on the basis of similar weight and overall body condition. No other medication was administered during the study period.

The hoggets were assigned randomly, on the basis of faecal egg count (FEC) and egg identification, to one of the following groups:

Group 1: Control (untreated)

Group 2: Positive Control (T1)

Group 3: Test (T2)

Group 4: Test (T3)

The hoggets were maintained together throughout the trial.

Treatment

Group 1: No treatment

Group 2: Hoggets were treated in accordance with Ivomec Batch 6639105 Exp. 01/95 label, ie 1 mL per 4 kg bodyweight (providing a dose of 200 μg Ivermectin per kg bodyweight)--T1

Group 3: Hoggets were treated with 1 mL Speedwell Mineral Drench Batch XIV-12 per 5 kg bodyweight (providing 200 μg Abamectin per kg bodyweight)--T2

Group 4: Hoggets were treated with 1 mL Speedwell P Mineral Drench Batch XIV-18 per 5 kg bodyweight (providing 200 μg Abamectin and 3.76 mg Praziquantel per kg bodyweight)--T3

Trial Activity and Design

Day-1 A group of 32 hoggets on the basis of similarity of bodyweight, overall body condition and health status were selected. A faecal egg count on all animals was carried out.

Day 0 On the basis of faecal egg count allocation was made randomly 8 animals to each group.

Day 1 Treatment of hoggets as follows:

Group 1: No treatment

Group 2: Ivomec treatment--T1

Group 3: Speedwell Mineral Drench Treatment--T2

Group 4: Speedwell P Mineral Drench Treatment--T3

Day 9 Faecal egg count on all hoggets.

Live weights taken.

Day 12 Hoggets slaughtered.

Removal of abomasum, and small and large intestines. Worms recovered, identified and counted.

Lungs were also examined for the presence of lungworm.

Parameters

Parameters for evaluation of Speedwell Mineral Drench and Speedwell P Mineral Drench efficacy and comparison with Ivomec treated and control groups were body weight, total egg count and total abomasal, intestine and lung worm count.

Assessment

Assessment was made by the clinical investigator. On the basis of satisfactory egg count on Day 9 total abomasal, intestine and lung counts proceeded.

Parasitology Analysis

Target parasite species were Haemonchus, Ostertagia, Trichostrongulus, Cooperia, Nematodirus, Oesophagostomum, Chabertis and Monezia expansa.

Total faecal egg count and necropsy procedures were performed by New Zealand Ministry of Agriculture and Fisheries Ruakura Animal Health Laboratory, Hamilton, New Zealand using approved and consistent methods and blind evaluation.

Results

The results of the trial are shown in tables 4-7 below.

Key for Tables 4-7:

Strong. Strongulus

Nema. Nematodirus

Haem. Haemonchus

Ostert. Ostertagia

Trich. Trichostrongulus

Coop. Cooperia

Scholex. Heads of Monezia expansa

Seg.mLs Segments (tape-like) of M expansa measured as millilitres

                                      TABLE 4                                      __________________________________________________________________________     Group 1 Control - No Treatment                                                 TAG WGT. DOSE                                                                               START    POST DOSE                                                                              12 DAY CRITICAL SLAUGHTER WORM COUNTS                                                                  MONIEZA                  No. kg.  ml. Strong.                                                                             Nema.                                                                              Strong.                                                                            Nema.                                                                              Haem.                                                                              Ostert.                                                                            Trich.                                                                             Nema.                                                                              Trich.                                                                             Coop.                                                                              Scholex                                                                            Seg.mls.             __________________________________________________________________________     19  20   --  2100 --  1300                                                                               --  --  100  2800                                                                              --  23200                                                                              5200                                                                               --  --                     36 22 -- 3100 --  300 -- -- 100  1900 --  6000  700 -- --                       7 22 -- 3100 50 2450 -- -- 300  2200 200 14500 2800 4 30                      35 24 -- 2950 --  1650 -- 100 700 13000 --  30000 4200 5 --                    28 23 -- 2300 -- 1050 -- --  600  8800 -- 20800 1600 --  --                     2 21 -- 2250 -- 1300 -- -- --  2500 100  9200 2000 4 25                       39 28 -- 1700 --  800 -- -- 200 10200 --  14400 2600 --  --                    31 22 -- 1550 -- 1700 -- -- 200  2800 -- 17200  800 --  3                      MEAN   2681 6.25 1318 -- 12.5 275  5825 37.5 16912 2487 1.6 725              __________________________________________________________________________

                                      TABLE 5                                      __________________________________________________________________________     Group 2 - IVOMEC (T1)                                                          TAG WGT. DOSE                                                                               START    POST DOSE                                                                              12 DAY CRITICAL SLAUGHTER WORM COUNTS                                                                  MONIEZIA                 No. kg.  ml. Strong.                                                                             Nema.                                                                              Strong.                                                                            Nema.                                                                              Haem.                                                                              Ostert.                                                                            Trich.                                                                             Nema.                                                                              Trich.                                                                             Coop.                                                                              Scholex                                                                            Seg.mls              __________________________________________________________________________      6  21   5.0 3350 --  --  --  --  --  --  --  --  --  --  --                     18 18 4.5 3050 -- -- -- -- -- -- -- -- -- -- --                                33 22 5.5 2850 -- -- -- -- -- -- -- -- -- 1 1                                  40 24 6.0 2350 50 -- -- -- -- -- -- -- -- --  --                               42 20 5.0 2100 -- -- -- -- -- -- -- -- -- -- --                                17 26 6.5 2250 -- -- -- -- -- -- -- -- -- -- --                                26 24 6.0 1150 -- -- -- -- -- -- -- -- -- 3 1                                  25 22 5.5 600 -- -- -- -- -- -- -- -- -- 8 32                                  MEAN   2212.5 6.25 -- -- -- -- -- -- -- -- 1.5 4.25                          PERCENTAGE (%)        99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               6.25                                                                               41.3                 __________________________________________________________________________

                                      TABLE 6                                      __________________________________________________________________________     Group 3 - Speedwell Mineral Drench (T2)                                        TAG WGT. DOSE                                                                               START   POST DOSE                                                                              12 DAY CRITICAL SLAUGHTER WORM COUNTS                                                                  MONIEZIA                  No. kg.  ml. Strong.                                                                            Nema.                                                                              Strong.                                                                            Nema.                                                                              Haem.                                                                              Ostert.                                                                            Trich.                                                                             Nema.                                                                              Trich.                                                                             Coop.                                                                              Scholex.                                                                            .Seg.mls             __________________________________________________________________________     41  18   3.5 6900                                                                               50  --  --  --  --  --  --  --  --  1    1                       5 24 5.0 3300 50 -- -- -- -- -- -- -- -- 3 --                                  3 22 4.5 3050 -- -- -- -- -- -- -- -- -- 7 13                                 12 22 4.5 2900 -- -- -- -- -- -- -- -- -- 3 30                                 15 24 5.0 2350 -- -- -- -- -- -- -- -- -- 14 4                                 21 22 4.5 4550 -- -- -- -- -- -- -- -- -- 5 2                                  38 22 4.5 1800 -- -- -- -- -- -- -- -- -- 2 105                                16 26 5.0 1550 -- -- -- -- -- -- -- -- -- --  --                               MEAN   2446 12.5 -- -- -- -- -- -- -- -- 4.37 19.37                          PERCENTAGE (%)       99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               --   --                   __________________________________________________________________________

                                      TABLE 7                                      __________________________________________________________________________     Group 4 - Speedwell P Mineral Drench (T3)                                      TAG WGT. DOSE                                                                               START    POST DOSE                                                                              12 DAY CRITICAL SLAUGHTER WORM COUNTS                                                                  MONIEZIA                 No. kg.  ml. Strong.                                                                             Nema.                                                                              Strong.                                                                            Nema.                                                                              Haem.                                                                              Ostert.                                                                            Trich.                                                                             Nema.                                                                              Trich.                                                                             Coop.                                                                              Scholex                                                                            .Seg.mls             __________________________________________________________________________      4  22   4.5 5800 --  --  --  --  --  --  --  --  --  --  --                     37 23 4.5 3000 50 -- -- -- -- -- -- -- -- -- --                                34 22 4.5 2800 -- -- -- -- -- -- -- -- -- -- --                                 9 22 4.5 2750 -- 1600 -- -- -- -- -- -- -- -- --                              13 20 4.0 2050 -- -- -- -- -- -- -- -- -- -- --                                23 27 5.5 1950 -- -- -- -- -- -- -- -- -- -- --                                20 26 5.0 650 -- -- -- -- -- -- -- -- -- -- --                                 32 24 5.0 700 -- -- -- -- -- -- -- -- -- -- --                                 MEAN   2462.5 6.25 200 -- -- -- -- -- -- -- -- --                            PERCENTAGE (%)        84.8                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                                                                               99.9                 __________________________________________________________________________

The data was analysed comparing treatment group means and in accordance with WAAVP guidelines.

The study compared the efficacies of Speedwell Mineral Drench Batch XIV-12 and Speedwell P Mineral Drench Batch XIV-18 based on pre- and post dosing FEC's and 12 day slaughter worm counts. When compared with Ivomec Batch 6639105 both products demonstrated 99.9% efficacy against nematodes when compared with the control group. Against Monezia expansa only Speedwell P Mineral Drench (containing praziquantel) demonstrated efficacy at 99.9%. Both Speedwell Mineral Drench and Ivomec were ineffective.

INDUSTRIAL APPLICATION

The veterinary compositions of the invention have been shown to be stable, non-toxic and effective in the treatment of endo- and ectoparasites in animals including but not limited to sheep, cattle, goats, and horses.

ADVANTAGES

It is advantageous to combine two or more anthelmintics with different activity in one composition to obtain a broad spectrum activity.

It is also advantageous to the user as only one treatment is needed against a number of parasites instead of two or more different treatments. This reduces the amount of time spent treating animals and therefore reduces stress to the animals themselves.

VARIATIONS

Although the above examples have concentrated on the use of praziquantel combined with abamectin or ivermectin, any other compound of the avermectin group could also be used.

In forming the compositions of the invention the active anthelmintic ingredients are dissolved in a solvent. In some instances it is preferred to thicken the resulting solution by absorbing it onto a solid carrier. These thickened solutions are also within the scope of the invention.

Finally, it will be appreciated that various other alterations and modifications may be made to the foregoing without departing from the scope of this invention. 

What is claimed is:
 1. A stable veterinary liquid anthelmintic composition suitable for administration to warm-blooded non-human animals at a dose of more than 2.0 mg of praziquantel per kilogram of body weight comprising:a) an effective amount of praziquantel; b) an effective amount of at least one macrolide anthelmintic selected from the group comprising the avermectins and the milbemycins; and c) a suitable organic solvent comprising an ester or ester like compound that dissolves praziquantel and the avermectin or milbemycin and is not toxic to animals.
 2. A stable veterinary liquid anthelmintic composition as claimed in claim 1 wherein the organic solvent is selected from the group consisting of glycerol formal, ethyl lactate, benzyl alcohol and N-methyl-2-pyrrolidone and the like.
 3. A stable veterinary liquid anthelmintic composition as claimed in claim 2 wherein the composition is further dissolved in a carrier selected from the group consisting of monopropylene glycol, oil, water and the like.
 4. A stable veterinary liquid anthelmintic composition as claimed in claim 3 wherein the macrolide anthelmintic is ivermectin present in the range 0.1 to 0.2% w/v.
 5. A stable veterinary liquid anthelmintic composition as claimed in claim 4 wherein the organic solvent includes both glycerol formal and benzyl alcohol.
 6. A stable veterinary liquid anthelmintic composition as claimed in claim 5 wherein the carrier is monopropylene glycol.
 7. A stable veterinary liquid anthelmintic composition as claimed in claim 6 wherein the composition also contains minerals.
 8. A stable veterinary liquid anthelmintic composition as claimed in claim 3 wherein the macrolide anthelmintic is abamectin present in the range 0.1 to 2.0% w/v.
 9. A stable veterinary liquid anthelmintic composition as claimed in claim 8 wherein the organic solvent includes both glycerol formal and benzyl alcohol.
 10. A stable veterinary liquid anthelmintic composition as claimed in claim 9 wherein the carrier is monopropylene glycol.
 11. A stable veterinary liquid anthelmintic composition as claimed in claim 10 wherein the composition also contains minerals.
 12. A stable veterinary liquid anthelmintic composition as claimed in claim 3 wherein the macrolide anthelmintic is present in the range from 0.1-2% w/v and the praziquantel is present in the range from 1 to 15% w/v.
 13. A method for the treatment of endo- and ectoparasites in a non-human animal by administrating to an animal at the rate of 1 mL/5-20 kg of body weight a stable liquid composition comprising:a) an effective amount of praziquantel; b) an effective amount of at least one macrolide anthelmintic selected from the group comprising the avermectins and the milbemycins; and c) a suitable organic solvent comprising an ester or ester like compound that dissolves praziquantel and the avermectin or milbemycin and is not toxic to animals;wherein the organic solvent is selected from the group consisting of glycerol formal, ethyl lactate, benzyl alcohol and N-methyl-2-pyrrolidone and the like; and wherein the composition is further dissolved in a carrier selected from the group consisting of monopropylene glycol, oil, water and the like.
 14. A method for the treatment of endo- and ectoparasites in a non-human animal as claimed in claim 13 wherein the stable liquid composition is administered to animal as a drench or by injection.
 15. A stable veterinary anthelmintic paste composition suitable for administration to warm-blooded non-human animals at a dose of more than 2.0 mg of praziquantel per kilogram of body weight, comprising:a) a solution of an effective amount of praziquantel; and b) an effective amount of at least one macrolide anthelmintic selected from the group comprising the avermectins and the milbemycins; and c) a solvent comprising a ester or ester like compound that dissolves praziquantel and the avermectin or milbemycin and is not toxic to animals; and d) a thickener.
 16. A stable veterinary anthelmintic paste composition as claimed in claim 15 wherein the thickener is a solid carrier onto which the solution is absorbed and selected from the group comprising oat meal flour, methancel and xanthan gum.
 17. A stable veterinary anthelmintic paste composition as claimed in claim 16 wherein the praziquantel is present in the range from 1-15% w/v.
 18. A stable veterinary anthelmintic paste composition as claimed in claim 17 wherein the paste also includes a wax.
 19. A stable veterinary anthelmintic paste composition as claimed in claim 18 wherein the wax is diethyl glycol palmite stearate.
 20. A stable veterinary anthelmintic paste composition as claimed in claim 19 wherein the macrolide anthelmintic is abamectin present in the range 0.1 to 2.0% w/v.
 21. A stable veterinary anthelmintic paste composition as claimed in claim 20, containing enough praziquantel that it is suitable for administration at a dose rate of from 2.5 mg to 10 mg of praziquantel per kilogram of body weight of the animal.
 22. A method for the treatment of endo- and ectoparasites in a non-human animal by administering a paste formulation at the rate of 1 ml of paste for every 5 to 20 kg of body weight of the animal, the paste formulation comprising:a) a solution of an effective amount of praziquantel; and b) an effective amount of at least one macrolide anthelmintic selected from the group comprising the avermectins and the milbemycins; and c) a solvent comprising a ester or ester like compound that dissolves praziquantel and the avermectin or milbemycin and is not toxic to animals; and d) a thickener;wherein the thickener is a solid carrier onto which the solution is absorbed and selected from the group comprising oat meal flour, methancel and xanthan gum; wherein the praziquantel is present in the range from 1-15% w/v; wherein the paste also includes a wax; wherein the wax is diethyl glycol palmite stearate; and wherein the macrolide anthelmintic is abamectin present in the range 0.1 to 2.0% w/v. 